Chem. Pharm. Bull. 53(8) 1043—1047 (2005)

genesis of ischemia and reperfusion injury in the myocardium. Recent studies have suggested that a massive Ca influx may occur as a consequence of Na –Ca exchange via the sodium–calcium exchanger (NCX) during reperfusion which, in turn, may be caused by an accumulation of Na via the sodium–hydrogen exchanger (NHE) during ischemia. This results in an intracellular Ca overload, the detrimental effects of which include myocardial contracture, stunning, necrosis, and reperfusion arrhythmia. NCX functions in both reverse and forward modes, and it is well known that an overactive reverse NCX causes Ca overload. Inhibition of reverse NCX overactivity would effectively block this overload and prevent damage to the myocardium in ischemiareperfusion. Therefore, reverse NCX inhibitors are currently considered to be beneficial in treating disease states. Recently, quinazoline derivatives and a series of benzyloxyphenyl derivatives have been identified as NCX inhibitors. KB-R7943 (1) is one of the most widely known NCX inhibitors, and is used as a tool in heart and renal failure models, and SEA0400 (2) is well known as a potent reverse NCX inhibitor that is efficacious in myocardial ischemia-reperfusion injury (Fig. 1). We have recently discovered reverse NCX inhibitors, such as 3, which we have reported elesewhere. To create potent and selective reverse NCX inhibitors, we have now designed a novel class of NCX inhibitors based on 3, and in this paper describe the results of our work on the synthesis and structure–activity relationships (SAR) of this novel class of benzyloxyphenyl derivatives.